Antiarrhytmic benzylimidazole

ABSTRACT

Benzylazole derivatives being useful as antiarrhythmic agent are obtained by reacting the corresponding 2,3-epoxypropyloxybenzylazole with a primary or secondary amine.

The present invention relates to benzylazole derivatives being useful asantiarrhythmics.

The benzylazole derivatives are represented by the formula: ##STR1##(wherein A is a 5- or 6-membered unsaturated heterocycle containing 1-3nitrogen atoms or a benzimidazolyl optionally each substituted by 1-3substituents selected from oxo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₂ -C₆alkoxycarbonyl and halogen;

B is >CHR³ or >C═CR⁴ R⁵ in which R³, R⁴ and R⁵ are independentlyhydrogen or C₁ -C₄ alkyl;

R¹ is C₁ -C₄ alkyl;

R² is hydrogen or C₁ -C₄ alkyl; or ##STR2## is pyrrolidinyl, piperidino,piperazino or morpholino; and X, Y and Z are independently hydrogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy or halogen)

and pharmaceutically acceptable acid addition salts thereof are includedin the present invention.

The terms used in the above definition are illustratively exemplifiedbelow:

C₁ -C₄ alkyl includes methyl, ethyl, propyl, i-propyl, butyl, i-butyl,s-butyl, t-butyl;

C₁ -C₄ alkoxy includes methoxy, ethoxy, propoxy, i-propoxy, butoxy,i-butoxy;

C₂ -C₆ alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl;

halogen includes fluorine, chlorine, bromine, iodine; the 5- or6-membered unsaturated heterocycle containing 1-3 nitrogen atomsincludes pyrrole, imidazole, triazole, pyridine, pyridazine, pyrimidine,pyrazine, triazine, on which 1-3 substituents selected from oxo, C₁ -C₄alkyl, C₂ -C₆ alkoxycarbonyl and halogen may optionally exist.

The pharmaceutically acceptable acid addition salts of Compounds Iillustratively include salts with inorganic acids such as sulfuric acid,hydrochloric acid, hydrobromic acid or phosphoric acid and those withorganic acids such as acetic acid, citric acid, maleic acid, malic acid,succinic acid, tartaric acid, cinnamic acid, benzoic acid,methanesulfonic acid or ascorbic acid.

Compound I is prepared by the following reaction scheme: ##STR3##(wherein A, B, R¹, R², X, Y and Z have the same significance as givenearlier; and Q is halogen (e.g. chlorine, bromine, iodine) or leavinggroup (e.g. tosyloxy)).

Accordingly Compound I is prepared by reacting the phenol derivative(III) with an epihalohydrin or 2,3-epoxypropyl ester (V) and reactingthe resulting epoxide (II) with a primary or secondary amine (IV). Abovesteps are explained in detail below:

Step (a)

The phenol derivative (III) is reacted with an epihalohydrin (e.g.epibromohydrin, epichlorohydrin) or 1,2-epoxypropyl ester (e.g.2,3-epoxypropyl tosylate) (V) in the presence of a base such as alkalihydroxide, alkali hydrogencarbonate, alkali carbonate, alkali alkoxideor alkali hydride in an appropriate solvent such as methanol, ethanol,benzene, toluene, dimethylformamide, dimethylsulfoxide at roomtemperature to the boiling point of the solvent used (e.g. 15° to 120°C.).

Step (b)

The resulting epoxide (II) is reacted with a primary or secondary amine(IV) such as methylamine, ethylamine, i-propylamine, butylamine,i-butylamine, s-butylamine, t-butylamine, dimethylamine,methylethylamine, diethylamine, dipropylamine, di-i-propylamine,methylbutylamine, methyl-i-butylamine, or ethylbutylamine in thepresence or absence of an appropriate solvent such as alcohols (e.g.methanol, ethanol), ethers (e.g. ether, tetrahydrofuran), orhydrocarbons (e.g. benzene, toluene, xylene) at room temperature to theboiling point of the solvent used (e.g. about 25° to about 100° C.). Ingeneral, an excessive amount of the amine (IV) may play a role of thesolvent.

The starting phenol (III) is prepared according to the following scheme:##STR4## wherein W is halogen (e.g. chlorine, bromine, iodine) and A,R⁴, R⁵, X, Y and Z have the same significance as given earlier.

At first Compound IIIa is prepared by reacting an acetophenonederivative (VI) with a thionyl or carbonyl compound (VII) in anappropriate solvent (e.g. methylene chloride, 1,2-dichloroethane,dimethylsulfoxide, acetonitrile, dimethylformamide) at room temperatureor under cooling or heating, preferably at 10° to 60° C. For example,2-[1-(1-imidazolyl)vinyl]phenol is disclosed by Ogata et al.[Tetrahydron Letters, 52, 5011 (1979)] and2-[1-(1-benzimidazolyl)vinyl]phenol is disclosed by Ogata et al.[Synthetic Communications, 10 (7), 559 (1980)].

Then Compound IIIb in which B is alkylene is prepared by hydrogenatingCompound IIIa in a conventional manner.

Another starting compound (IIIc) is prepared as follows: ##STR5##(wherein W' is a reactive group such as halogen or ester moiety (e.g.tosyloxy); and A, X, Y and Z have the same significance as givenearlier). Thus the reaction of Compound VIII with Compound IX isperformed in an appropriate solvent (e.g. dimethylformamide, benzene,chloroform, tetrahydrofuran, diglyme, dimethylsulfoxide) in the presenceof a base such as triethylamine, pyridine, sodium amide, sodiumethoxide, or sodium hydride at room temperature to the boiling point ofthe solvent used. For example, o-(1-imidazolyl)methylphenol is disclosedin Japanese Unexamined Patent Publication No. 164677/1980.

A preferred compound of Compound I is shown by the formula: ##STR6##(wherein E and E' are independently hydrogen, C₁ -C₂ alkyl or C₂ -C₃alkoxycarbonyl;

R is C₃ -C₄ alkyl; and

X and Y are independently hydrogen, methyl, methoxy or chlorine).

Compound I thus obtained and its pharmaceutically acceptable acidaddition salts show excellent antiarrhythmic activity. Results of thepharmacological tests are shown below:

1. TEST METHOD (a) Antiarrhythmic activity (cardiomuscular action to themaximal stimulus frequency)

A certain number of atrium dextrum specimens were made by extracting theheart from male and female guinea-pigs weighing on average 350 to 600 g,and then suspended and fixed in a glass vessel filled withKrebs-Ringer-sodium carbonate solution (30° C.) in which a mixture of95% oxygen and 5% carbon dioxide was continuously introduced. Theautomatism of the specimens was recorded on the oscillograph. Maximalstimulus frequency was confirmed by affording a stimulus of the atriumdextrum from the exciting electrode equipped to a retainer.

After previously treating with a test compound for 10 minutes, thereducing percent (%) of the maximal stimulus frequency was calculated byobserving the reduction of the maximal frequency [Dawes, G. S.: Brit. J.Pharmacl., 1, 90 (1946)].

(b) Acute toxicity

Lethal dose was obtained by administering a test compound in the form ofa physiological brine solution into the tail venae of SLC-DDY male miceweighing from 25 to 35 g and calculating the value of LD₅₀ by the up anddown method [Brownlee, K. A. et al.: J. Am. Stat. As., 48, 262 (1953)].

2. RESULT

Table 1 shows the result of the tests, but Test Compound No. correspondsto Example No. in which the compound is prepared.

                  TABLE 1                                                         ______________________________________                                        Test        Reducing percent                                                  Compound    (%) of Maximal                                                                              Acute toxicity                                      No.         stimulus frequency                                                                          (mg/kg)                                             ______________________________________                                         7          38.1          19.8                                                13          34.5          15.5                                                17          31.7          36.4                                                22          35.8          26.5                                                24          36.1          36.4                                                25          39.2          22.3                                                26          35.8          33.9                                                29          29.0          30.0                                                30          50.6          28.5                                                31          42.8          36.4                                                Quinidine   22.8          53.6                                                ______________________________________                                    

As clearly shown from the above test results, Compound I obtained in thepresent invention shows excellent antiarrhythmia activity and is usefulfor treating arrhythmia or prophylaxis of angina pectoris. FurtherCompound I is available for treating thrombosis or the like diseases,showing platelet aggregation inhibitory activity.

Compound I may be administered enterally or parenterally and formulatedin combination with appropriate carriers, diluents, and/or excipients.Customary formulations such as powders, granules, tablets, or capsulesfor oral administration may be prepared in combination withpharmaceutically acceptable diluents, carriers and/or excipients such aslactose, sucrose, starch, cellulose, talc, magnesium stearate, magnesiumoxide, calcium sulfate, gum arabic, gelatin, sodium arginate, sodiumbenzoate or stearic acid. Injections may be prepared in combination withdistilled water, physiological brine or Ringer solution. Appropriatedosage of Compound I to human adults is daily about 5 to about 500 mgper os and about 20 to about 400 mg at one time for intravenousadministration.

Presently-preferred and practical embodiments of the present inventionare illustratively shown in the following examples.

EXAMPLE 1

1-{2,4-Dichloro-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol##STR7##

2,4-Dichloro-6-[1-(1-imidazolyl)vinyl]phenol (III₁) (3.9 g) is dissolvedin dry dimethylformamide (47 ml), to which 5% sodium hydride (1.10 g) isadded and then a solution of epibromohydrin (3.14 g) in drydimethylformamide (2 ml) is added dropwise. The solution is stirred at60° C. for 1.5 hours, then poured into water and extracted with benzene.The extract is washed with water, dried over sodium sulfate andevaporated to remove the benzene. Oily residue (II₁) is mixed withisopropylamine (20 ml), stirred at 50° C. for 19 hours and evaporated toremove the isopropylamine. To the residue is added water and sodiumhydrogencarbonate and then the mixture is extracted with methylenechloride. The extract is washed with water, dried over sodium sulfateand evaporated to remove the solvent. The residue is chromatographed onalumina (Activity II). The fractions eluted with 2-3% methanol-methylenechloride are collected and evaporated to remove the solvent. The residueis washed with etherisopropyl ether and filtered to give the titlecompound (2.1 g) as colorless prisms, mp, 88°-90° C. Recrystallizationfrom ethyl acetate-isopropyl ether gives colorless prisms (1.78 g), mp,88.5°-90° C.

Anal. Calcd. for C₁₇ H₂₁ O₂ N₃ Cl₂ : Calcd.: C, 55.14; H, 5.72; N,11.35; Cl, 19.15; Found: C, 55.31; H, 5.67; N, 11.33; Cl, 18.89.

EXAMPLES 2-48

The same procedure as in Example 1 gives Compound I in Table 2.

The abbreviations shown below have the following meanings.

Im=1-imidazolyl

Py=1-pyrazolyl

Bim=1-benzimidazolyl

Tri=1-(1,2,4-triazolyl)

Pyd=1-(4-oxo-1,4-dihydropyridyl)

Me=methyl

Et=ethyl

i-Pr=isopropyl

i-Bu=isobutyl

t-Bu=t-butyl

d=decomposition

    __________________________________________________________________________     ##STR8##                                                                 

    __________________________________________________________________________    Example                                                                              Compound I                 Mp.   Molecular                                                                              Elemental Analysis           No.    A      B     R   X   Y  Z  (°C.)                                                                        Formula  C  H  N  Cl                  __________________________________________________________________________    2      Im     CCH.sub.2                                                                           t-Bu                                                                              H   H  H  Oil   C.sub.18 H.sub.25 O.sub.2                                                              68.54.3                                                                          7.99                                                                             13.32                                                                            --                                                                   68.31                                                                            8.22                                                                             12.85                                                                            --                  3      Im     "     i-Pr                                                                              H   H  H  "     C.sub.17 H.sub.23 O.sub.2                                                     N.sub.3. 64.66                                                                            7.85                                                                             13.31                                                                            --                                                          H.sub.2 O                                                                              64.73                                                                            7.73                                                                             12.95                                                                            --                  4      Im     "     i-Pr                                                                              3-Cl                                                                              H  H  79-84 C.sub.17 H.sub.22 O.sub.2 N.sub.3                                             Cl.      57.70                                                                            6.84                                                                             11.88                                                                            10.02                                                       H.sub.2 O                                                                              58.05                                                                            6.79                                                                             11.72                                                                            10.27               5      Im     "     t-Bu                                                                              2-Cl                                                                              4-Cl                                                                             H  135-136.5                                                                           C.sub.18 H.sub.23 O.sub.2 N.sub.3                                             Cl       56.26                                                                            6.03                                                                             10.93                                                                            18.45                                                                56.26                                                                            6.03                                                                             10.91                                                                            18.38               6      Im     "     i-Pr                                                                              4-Cl                                                                              H  H  66.5-67.5                                                                           C.sub.17 H.sub.22 O.sub.2 N.sub.3                                             Cl       60.80                                                                            6.60                                                                             12.51                                                                            10.56                                                                60.85                                                                            6.65                                                                             12.39                                                                            10.59               7      Im     "     i-Pr                                                                              2-Cl                                                                              5-Cl                                                                             H  117-122                                                                             C.sub.17 H.sub.21 O.sub.2 N.sub.3                                             Cl.sub.2 55.14                                                                            5.72                                                                             11.35                                                                            19.15                                                                54.91                                                                            5.51                                                                             11.17                                                                            19.13               8      Im     CH.sub.2                                                                            i-Pr                                                                              H   H  H  147.5(d)                                                                            C.sub.18 H.sub.25 O.sub.6                                                     N.sub.3. 50.20                                                                            5.90                                                                             8.78                                                                             --                                                          1/2 H.sub.2 O                                                                          50.21                                                                            6.03                                                                             8.83                                                                             --                  __________________________________________________________________________    Example                                                                              Compound I                 Mp    Molecular                                                                              Elemental Analysis           No.    A      B     R   X   Y  Z  (° C.)                                                                       Formula  C  R  N  Cl                  __________________________________________________________________________    9      Im     CCH.sub.2                                                                           Me  3-Cl                                                                              H  H  Oil   C.sub.15 H.sub.18 O.sub.2                                                     N.sub.3. 56.58                                                                            5.74                                                                             13.05                                                                            14.68                                                       1/6 CH.sub.2 Cl.sub.2                                                                  56.05                                                                            5.62                                                                             12.55                                                                            15.20               10     Im     CC(Me).sub.2                                                                        i-Pr                                                                              4-Cl                                                                              H  H  85-87 C.sub.19 H.sub.26 O.sub.2 N.sub.3                                             Cl       62.71                                                                            7.20                                                                             11.55                                                                            9.74                                                                 62.70                                                                            7.33                                                                             11.31                                                                            9.75                11     Im     CCHMe i-Pr                                                                              H   H  H  Oil   C.sub.18 H.sub.25 O.sub.2 N.sub.3                                             .        67.77                                                                            8.03                                                                             13.17                                                                            --                                                          1/5 H.sub.2 O                                                                          68.09                                                                            8.12                                                                             12.69                                                                            --                  12     Im     "     t-Bu                                                                              H   H  H  "     C.sub.19 H.sub.27 O.sub.2                                                     N.sub.3. 68.53                                                                            8.29                                                                             12.62                                                                            --                                                          1/5 H.sub.2 O                                                                          68.88                                                                            8.45                                                                             12.21                                                                            --                  13     Im     CCH.sub.2                                                                           i-Bu                                                                              2-Cl                                                                              5-Cl                                                                             H  104-105.5                                                                           C.sub.18 H.sub.23 O.sub.2 N.sub.3                                             Cl.sub.2 56.26                                                                            6.03                                                                             10.93                                                                            18.45                                                                56.44                                                                            5.98                                                                             10.92                                                                            18.44               14     Im     "     t-Bu                                                                              2-Cl                                                                              5-Cl                                                                             H  147.5-149.5                                                                         C.sub.18 H.sub.23 O.sub.2 N.sub.3                                             Cl.sub.2 56.26                                                                            6.03                                                                             10.93                                                                            18.45                                                                56.27                                                                            6.03                                                                             10.62                                                                            18.29               15     Py     "     i-Pr                                                                              H   H  H  66.5-67.5                                                                           C.sub.17 H.sub.23 O.sub.2                                                              67.75.3                                                                          7.69                                                                             13.94                                                                            --                                                                   67.78                                                                            7.92                                                                             14.03                                                                            --                  16     Py     "     i-Pr                                                                              4-Cl                                                                              H  H  131-132                                                                             C.sub.17 H.sub.22 O.sub.2 N.sub.3                                             Cl       53.59                                                                            5.68                                                                             9.87                                                                             8.32                                                        (COOH).sub.2                                                                           53.33                                                                            5.83                                                                             9.81                                                                             8.43                __________________________________________________________________________    Example                                                                              Compound I                 Mp    Molecular                                                                              Elemental Analysis           No.    A      B     R   X   Y  Z  (°C.)                                                                        Formula  C  H  N  Cl                  __________________________________________________________________________    17     4-EtOCO                                                                              "     i-Pr                                                                              H   H  H  Oil   C.sub.21 H.sub.29 O.sub.4 N.sub.                                              3.       63.33                                                                            7.64                                                                             10.55                                                                            --                         5-MeIm                           3/5 H.sub.2 O                                                                          63.65                                                                            7.72                                                                             10.18                                                                            --                  18     Im     "     i-Pr                                                                              2-Cl                                                                              H  H  64-66 C.sub.17 H.sub.22 O.sub.2 N.sub.3                                             Cl       60.80                                                                            6.60                                                                             12.51                                                                            10.56                                                                60.86                                                                            6.67                                                                             12.44                                                                            10.47               19     2-Et5- "     i-Pr                                                                              H   H  H  86.5-87                                                                             C.sub.20 H.sub.28 O.sub.2                                                              69.94.3                                                                          8.51                                                                             12.24                                                                            --                         MeIm                                      69.93                                                                            8.65                                                                             12.17                                                                            --                  20     2-MeIm "     i-Pr                                                                              H   H  H  65-66 C.sub.18 H.sub.25 O.sub.2                                                     N.sub.3. 66.27                                                                            8.10                                                                             12.88                                                                            --                                                          3/5 H.sub.2 O                                                                          66.23                                                                            7.99                                                                             12.85                                                                            --                  21     Bim    "     i-Pr                                                                              H   H  H  148-149(d)                                                                          C.sub.21 H.sub.25 O.sub.2 N.sub.3                                             .        61.32                                                                            6.26                                                                             9.33                                                                             --                                                          (COOH).sub.2.1/2H.sub.2 O                                                              61.85                                                                            6.64                                                                             9.03                                                                             --                  22     Bim    "     t-Bu                                                                              H   H  H  105-106                                                                             C.sub.22 H.sub.27 O.sub.2                                                              72.30.3                                                                          7.45                                                                             11.50                                                                            --                                                                   72.40                                                                            7.59                                                                             11.26                                                                            --                  23     2-MeIm "     t-Bu                                                                              H   H  H  70-71 C.sub.19 H.sub.27 O.sub.2                                                              69.27.3                                                                          8.26                                                                             12.76                                                                            --                                                                   69.14                                                                            8.46                                                                             12.66                                                                            --                  24     4-MeIm "     i-Pr                                                                              H   H  H  Oil*  C.sub.18 H.sub.25 O.sub.2                                                              68.54.3                                                                          7.99                                                                             13.32                                                                            --                                                                   68.21                                                                            8.19                                                                             12.65                                                                            --                  25     Py     "     t-Bu                                                                              H   H  H  75-76 C.sub.18 H.sub.25 O.sub.2                                                              68.54.3                                                                          7.99                                                                             13.32                                                                            --                                                                   68.43                                                                            8.11                                                                             13.40                                                                            --                  26     Im     "     i-Pr                                                                              2-Cl                                                                              3-Cl                                                                             H  124(d)                                                                              C.sub.17 H.sub.21 O.sub.2 N.sub.3                                             Cl.sub.2.                                                                              45.09                                                                            4.68                                                                             7.51                                                                             12.68                                                       2(COOH).sub.2.1/2 H.sub.2                                                              45.11                                                                            4.57                                                                             7.29                                                                             12.33               27     Im     "     i-Pr                                                                              3-Cl                                                                              5-Cl                                                                             H  Oil   C.sub.17 H.sub.21 O.sub.2 N.sub.3                                             Cl.sub.2 55.14                                                                            5.70                                                                             11.35                                                                            19.15                                                                54.83                                                                            5.73                                                                             10.75                                                                            18.96               28     Im     "     i-Pr                                                                              3-Cl                                                                              4-Cl                                                                             H  "     C.sub.17 H.sub.21 O.sub.2 N.sub.3                                             Cl.sub.2.                                                                              54.61                                                                            5.77                                                                             11.23                                                                            18.97                                                       1/5 H.sub.2 O                                                                          54.43                                                                            5.83                                                                             10.96                                                                            19.01               29     Im     "     i-Pr                                                                              2-OMe                                                                             H  H  "     C.sub.18 H.sub.25 O.sub.2                                                     N.sub.3. 64.84                                                                            8.16                                                                             12.60                                                                            --                                                          H.sub.2 O                                                                              64.75                                                                            7.92                                                                             12.02                                                                            --                  30     Im     "     i-Pr                                                                              2-Cl                                                                              5-Me                                                                             H  126(d)                                                                              C.sub.18 H.sub.24 O.sub.2 N.sub.3                                             Cl.      51.26                                                                            5.51                                                                             8.40                                                                             7.09                                                        5/3 (COOH).sub.2                                                                       50.77                                                                            5.61                                                                             8.24                                                                             7.15                31     Tri    "     i-Pr                                                                              H   H  H  156-157                                                                             C.sub.16 H.sub.22 O.sub.2                                                     N.sub.4. 55.09                                                                            6.17                                                                             14.28                                                                            --                                                          (COOH).sub.2                                                                           54.78                                                                            6.19                                                                             14.17                                                                            --                  32     Py     CH.sub.2                                                                            t-Bu                                                                              H   H  H  177-  C.sub.17 H.sub.25 O.sub.2                                                     N.sub.3. 57.74                                                                            6.94                                                                             10.63                                                                            --                                                    177.5(d)                                                                            (COOH).sub.2.                                                                          57.36                                                                            7.02                                                                             10.63                                                                            --                                                          1/10 H.sub.2 O                        33     Py     "     i-Pr                                                                              H   H  H  64-65 C.sub.16 H.sub.23 O.sub.2                                                              66.41.3                                                                          8.01                                                                             14.52                                                                            --                                                                   66.30                                                                            8.18                                                                             14.63                                                                            --                  34     Py     CCH.sub.2                                                                           t-Bu                                                                              4-Cl                                                                              H  H  107-109(d)                                                                          C.sub.18 H.sub.24 O.sub.2 N.sub.3                                             Cl.      54.61                                                                            5.96                                                                             9.55                                                                             8.06                                                        (COOH).sub.2                                                                           54.55                                                                            5.98                                                                             9.37                                                                             8.04                35     Bim    "     i-Pr                                                                              2-OMe                                                                             H  H  147-148(d)                                                                          C.sub.22 H.sub.27 O.sub.3                                                     N.sub.3. 60.67                                                                            6.24                                                                             8.85                                                                             --                                                          (COOH).sub.2.1/5H.sub.2 O                                                              60.51                                                                            6.08                                                                             8.81                                                                             --                  36     Bim    "     t-Bu                                                                              2-OMe                                                                             H  H  110-111                                                                             C.sub.23 H.sub.29 O.sub.3                                                              69.85.3                                                                          7.39                                                                             10.63                                                                            --                                                                   69.67                                                                            7.30                                                                             10.55                                                                            --                  37     Im     "     t-Bu                                                                              2-Cl                                                                              5-Me                                                                             H  131-132                                                                             C.sub.19 H.sub.26 O.sub.2 N.sub.3                                             Cl       62.71                                                                            7.20                                                                             11.55                                                                            9.74                                                                 62.64                                                                            7.15                                                                             11.46                                                                            9.88                38     Im     "     t-Bu                                                                              2-Me                                                                              H  H  145(d)                                                                              C.sub.19 H.sub.27 O.sub.2 N.sub.3                                             .        57.67                                                                            7.15                                                                             10.06                                                                            --                                                          (COOH).sub.2.5H.sub.2 O.                                                               57.96                                                                            6.76                                                                             10.22                                                                            --                                                          1/5 CH.sub.3 CN                       39     Im     "     t-Bu                                                                              2-Me                                                                              4-Cl                                                                             H  76-78(d)                                                                            C.sub.19 H.sub.26 O.sub.2 N.sub.3                                             Cl.      50.79                                                                            5.56                                                                             7.73                                                                             6.52                                                        2(COOH).sub.2                                                                          50.84                                                                            5.82                                                                             7.51                                                                             6.78                40     Im     "     i-Pr                                                                              2-Me                                                                              4-Cl                                                                             H  123-127(d)                                                                          C.sub.18 H.sub.24 O.sub.2 N.sub.3                                             Cl.      49.03                                                                            5.42                                                                             7.80                                                                             6.58                                                        2(COOH).sub.2.1/2H.sub.2 O                                                             48.78                                                                            5.18                                                                             7.51                                                                             6.48                41     Im     "     i-Pr                                                                              2-Cl                                                                              4-Me                                                                             5-Me                                                                             99-100.5                                                                            C.sub.19 H.sub.26 O.sub.2 N.sub.3                                             Cl       62.71                                                                            7.20                                                                             11.55                                                                            9.74                                                                 62.80                                                                            7.31                                                                             11.44                                                                            9.85                42     Im     "     t-Bu                                                                              2-Cl                                                                              4-Me                                                                             5-Me                                                                             129-130                                                                             C.sub.20 H.sub.28 O.sub.2 N.sub.3                                             Cl       63.57                                                                            7.47                                                                             11.12                                                                            9.38                                                                 63.51                                                                            7.51                                                                             10.91                                                                            9.44                43     Im     "     t-Bu                                                                              2-Me                                                                              5-Me                                                                             H  136.5-140                                                                           C.sub.20 H.sub.29 O.sub.2                                                              69.94.3                                                                          8.51                                                                             12.24                                                                            --                                                                   70.01                                                                            8.64                                                                             12.21                                                                            --                  44     Im     "     i-Pr                                                                              2-Me                                                                              5-Me                                                                             H  109-110                                                                             C.sub.19 H.sub.27 O.sub.2                                                              69.27.3                                                                          8.26                                                                             12.76                                                                            --                                                                   69.06                                                                            8.44                                                                             12.62                                                                            --                  45     Im     "     t-Bu                                                                              2-Me                                                                              4-Me                                                                             H  111-112                                                                             C.sub.20 H.sub.29 O.sub.2                                                              69.94.3                                                                          8.51                                                                             12.24                                                                            --                                                                   69.61                                                                            8.64                                                                             12.02                                                                            --                  46     Im     "     i-Pr                                                                              2-Me                                                                              4-Me                                                                             H  86-87 C.sub.19 H.sub.27 O.sub.2                                                              69.27.3                                                                          8.26                                                                             12.76                                                                            --                                                                   69.18                                                                            8.48                                                                             12.68                                                                            --                  47     Pyd    "     i-Pr                                                                              H   H  H  173.5-174.5                                                                         C.sub.19 H.sub.24 O.sub.3                                                     N.sub.2. 57.01                                                                            5.87                                                                             6.04                                                                             --                                                    (d)   3/2(COOH).sub.2                                                                        56.95                                                                            5.89                                                                             5.97                                                                             --                  __________________________________________________________________________     *2(COOH).sub.2.1/2CH.sub.3 CN salt mp. 59-63° C. (d)              

REFERENCE 1

Preparation of 2-[1-(1-pyrazolyl)vinyl]phenol ##STR9##

Pyrazole (9 g) is suspended in methylene chloride (45 ml), to whichthionyl chloride (3.93 g) is added dropwise at 0° C. with stirring.o-Hydroxyacetophenone (3 g) is also added thereto after 10 minutes. Themixture is stirred at room temperature for 4 hours, then ice water isadded thereto, and extracted with methylene chloride after beingneutralized with an aqueous solution of sodium hydrogencarbonate. Theextract is washed with water, dried over sodium sulfate and evaporatedto remove the solvent. The residue is chromatographed on silica gel andeluted with 1-2% methanol-methylene chloride to give the title compound(198 mg). Recrystallization from ethyl acetate-petroleum ether givescrystals melting at 107.5°-109° C.

Anal. Calcd. for C₁₁ H₁₀ ON₂ ; Calcd.: C, 70.95; H, 5.41; N, 15.05;Found: C, 71.25; H, 5;34; N, 15.24.

The above compound is used as starting compound in Examples 15 and 25.

Starting compounds in other examples are prepared in the same manner.Melting points of new compounds are shown as follows:

    ______________________________________                                         ##STR10##                     III                                            Related                                                                              Compound III               Mp                                          Example                                                                              A         B          X     Y    Z    (°C.)                      ______________________________________                                        1,5    Im        CHCH.sub.2 2-Cl  4-Cl H    216-                                                                          217                               4,9    Im        "          3-Cl  H    H    175-                                                                          178                               6      Im        "          4-Cl  H    H    182-                                                                          183                               7,13,14                                                                              Im        "          2-Cl  5-Cl H    182-                                                                          184                               10     Im        CHC(Me).sub.2                                                                            4-Cl  H    H    190-                                                                          194                               11,12  Im        CHCHMe     H     H    H    182-                                                                          186.5                             16,34  Py        CHCH.sub.2 4-Cl  H    H    140-                                                                          142.5                             17     4-EtOCO-  "          H     H    H    216-                              5-MeIm                                 218                                    18     Im        "          2-Cl  H    H    149-                                                                          151.5                             19     2-Et5-    "          H     H    H    212-                                     MeIm                                 213                               20,23  2-MeIm    "          H     H    H    170-                                                                          172                               24     4-MeIm    "          H     H    H    165-                                                                          170                               26     Im        "          2-Cl  3-Cl H    207-                                                                          209                               27     Im        "          3-Cl  5-Cl H    193-                                                                          194                               28     Im        "          3-Cl  4-Cl H    252-                                                                          253.5                             29     Im        "          2-OMe H    H    153-                                                                          154                               30,37  Im        "          2-Cl  5-Me H    152.5-                                                                        153.5                             31     Tri       "          H     H    H    153-                                                                          156                               35,36  Bim       "          2-OMe H    H    192-                                                                          193(d)                            38     Im        "          2-Me  H    H    141-                                                                          143                               39,40  Im        "          2-Me  4-Cl H    160-                                                                          161.5                             41,42  Im        "          2-Cl  4-Me 5-Me 152-                                                                          153                               43,44  Im        "          2-Me  5-Me H    130-                                                                          131                               45,46  Im        "          2-Me  4-Me H    134-                                                                          135                               ______________________________________                                    

REFERENCE 2

o-(1-Pyrazolylmethyl)phenol ##STR11##

Pyrazole (24.68 g) is mixed with dry methylene chloride (123 ml), towhich thionyl chloride (10.78 g) is added with stirring under icecooling. The mixture is stirred for 10 minutes and o-hydroxybenzylalcohol (7.5 g) is added thereto. The mixture is stirred at roomtemperature for 1.5 hours, then neutralized with an aqueous solution ofsodium hydrogencarbonate and extracted with methylene chloride. Theextract is washed with water, dried and evaporated to remove thesolvent. The residue is chromatographed on silica gel. Eluates withbenzene-methylene chloride are collected, evaporated to remove thesolvent, washed with ethyl acetate-isopropyl ether, and filtered to givethe title compound (5.95 g), mp. 123°-124° C.

Anac. Calcd. for C₁₀ H₁₀ ON₂ : Calcd.: C, 68.95; H, 5.79; N, 16.08;Found: C, 69.23; H, 5.74; N, 16.11.

The above compound is used as starting compound in Examples 32 and 33.

REFERENCE 3

Preparation of 1-[1-(2-hydroxyphenyl)vinyl]4-pyridone ##STR12##

4-Hydroxypyridine (838 mg) is mixed with a mixture of triethylamine (890mg) and dry methylene chloride (8.4 ml) and stirred under cooling. Asolution of thionyl chloride (1.048 g) in methylene chloride (3 ml) isadded dropwise thereto at a temperature maintained at about 10° C. andthen the mixture is stirred for an additional 30 minutes and addeddropwise to a mixture of o-hydroxyacetophenone (1 g), triethylamine (890mg) and dry methylene chloride (10 ml) at the same temperature withstirring. The resultant mixture is stirred at room temperature for 15.5hours and then ice water is added thereto. The mixture is made alkalinewith sodium hydrogencarbonate and extracted with methylene chloride. Theextract is washed with water, dried and evaporated to remove thesolvent. The residue is chromatographed on silica gel. Eluates with 7%methanol-methylene chloride are collected and evaporated to remove thesolvent. The yielded crystals are recrystallized from methanol-ethylacetate to give the title compound (436 mg), mp. 201°-203° C.

Anal. Calcd. for C₁₃ H₁₁ O₂ N: Calcd.: C, 73.22; H, 5.20; N, 6.57;Found: C, 73.17; H, 5.09; N, 6.54.

The above compound is used as a starting compound in Example 47.

EXAMPLE 48

1-{2-[1-(1-imidazolyl)vinyl]phenoxy}-3-(1-pyrrolidono)-2-propanol##STR13##

A mixture of 2-[1-(1-imidazolyl)vinyl]phenol (4 g), 50% sodium hydroxide(1.55 g), dimethyl formamide (20 ml) and epibromohydrin (4.41 g) isheated at 50° C. for 1 hour with stirring. The reaction mixture istreated in the same manner as in Example 1. The resultant epoxide iskept at room temperature for 20 hours after addition of pyrrolidine (6ml) and then evaporated to remove the pyrrolidone. The residue is mixedwith benzene and evaporated to remove the solvent. The residue ischromatographed on alumina. The eluates with 2% methanol-methylenechloride are collected and evaporated to remove the solvent. The residueis recrystallized from ethyl acetate-isopropyl ether to give the titlecompound (720 mg), mp. 74°-76° C.

Anal. Calcd. for C₁₈ H₂₃ O₂ N₃ : Calcd.: C, 68.94; H, 7.40; N, 13.41;Found: C, 69.00; H, 7.44; N, 13.37.

EXAMPLE 49

1-{2-[1-(1-imidazolyl)vinyl]phenoxy}-3-dimethylamino-2-propanol##STR14##

The same procedure as in Example 48 gives the title compound, mp.62.5°-63.5° C.

Anal. Calcd. for C₁₆ H₂₁ O₂ N₃ : Calcd.: C, 66.87; H, 7.37; N, 14.62;Found: C, 66.73; H, 7.33; N, 14.66.

EXAMPLE 50

1-{2-[1-(1-imidazolyl)ethyl]phenoxy}-3-isopropylamino-2-propanol##STR15##

The same procedure as in Example 1 is practised with6-[1-(1-imidazolyl)ethyl]phenol (1.0 g), 50% sodium hydride (385 mg),dehydrated dimethylformamide (10 ml) and epibromohydrin (1.10 g) to givean epoxide, which is mixed with isopropylamine (8 ml) and refluxed for 1hour. The reaction mixture is treated in the usual manner and theresultant residue is chromatographed on alumina (activity III). Theeluates with 1-3% methanol-methylene chloride are collected andevaporated to remove the solvent. The title compound (618 mg) is yieldedas an oil.

Anal. Calcd. for C₁₇ H₂₅ O₂ N₃.3/5H₂ O; Calcd.: C, 64.98; H, 8.40; N,13.37; Found: C, 65.22; H, 8.45; N, 12.92.

REFERENCE 4

2-[1-(1-imidazolyl)ethyl]phenol ##STR16##

A mixture of 6-[1-(1-imidazolyl)vinyl]phenol (500 mg), methanol (20 ml),14% hydrochloric acid-methanol (5 ml) and platinum oxide monohydrate(100 mg) is stirred in a hydrogen atmosphere and filtered when hydrogenabsorption is finished, about 1.5 hours later. The filtrate iscondensed, neutralized with an aqueous solution of sodiumhydrogencarbonate and extracted with methylene chloride. The extract iswashed with water, dried and evaporated to remove the solvent. Theresidue is recrystallized from ethyl acetate-isopropyl ether to give thetitle compound (456 mg), mp. 170.5°-172° C.

Anal. Calcd. for C₁₁ H₁₂ ON₂ : Calcd.: C, 70.18; H, 6.43; N, 14.88;Found: C, 70.25; H, 6.51; N, 14.78.

The product is used as starting compound in Example 50.

What is claimed is:
 1. A compound of the formula: ##STR17## wherein Eand E' each is hydrogen, C₁ -C₂ alkyl or C₂ -C₃ alkoxycarbonyl;R is C₃-C₄ alkyl; and X and Y each is hydrogen, methyl, methoxy or chlorine; ora pharmaceutically acceptable acid addition salt thereof.
 2. A compoundaccording to claim 1, namely1-{2,5-dichloro-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol.3. A compound according to claim 1, namely1-{2,5-dichloro-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-t-butylamino-2-propanol.4. A compound according to claim 1, namely1-{2,5-dichloro-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isobutylamino-2-propanol.5. A compound according to claim 1, namely1-{2-[1-(4-ethoxycarbonyl-5-methylimidazol-1-yl)vinyl]phenoxy}-3-isopropylamino-2-propanol.6. A compound according to claim 1, namely1-{2-[1-(2-methyl-1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol.7. A compound according to claim 1, namely1-{2,3-dichloro-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol.8. A compound according to claim 1, namely1-{2-methoxy-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol9. A compound according to claim 1, namely1-{2-chloro-5-methyl-6-[1-(1-imidazolyl)vinyl]phenoxy}-3-isopropylamino-2-propanol.10. A pharmaceutical composition for treating arrhythmia comprising anantiarrhythmically effective amount of the compound claimed in claim 1and a pharmaceutically acceptable diluent, carrier or excipient.
 11. Amethod for treating a patient suffering from arrhythmia which comprisesadministering to said patient the pharmaceutical composition as claimedin claim 1.